New aminophenylamidines, their production and their medicinal use

ABSTRACT

4-Amino substituted phenylamidine are anthelmintics. The compounds, of which N-(4-aminophenyl)-N&#39;&#39;,N&#39;&#39;-dimethylacetamidine is a representative embodiment, can be prepared through treatment of a 4-amino aniline with a carboxylic acidamide or thioamide, reduction of an appropriately substituted 4-aminophenylamidine, optionally followed by alkylation of the resultant 4-aminophenylamidine, formation of a Schiff base followed by quaternization and hydrolysis, or hydrolysis of a 4-acylaminophenylamidine.

United States Patent Wollweber et al.

NEW AMINOPHENYLAMIDINES, THEIR PRODUCTION AND THEIR MEDICINAL USE Inventors: Hartmund Wollweber, Wuppertal,

Germany; Winfried Flucke. Beenleigh, Australia Assignee: Bayer Aktiengesellschaft, Germany Filed: Oct. 17, 1974 Appl. No.: 515,576

Related US. Application Data Division of Ser. No 399,813, Sept 24, I973 which is a division of Ser. No. [51571 June 9, I97 I, Pat. No. 3,855,292.

Foreign Application Priority Data June l3, I970 Germany 2029299 US. Cl 260/564 RF; 26()/5()l.l4

Int. Cl. i i i i i i i C07C 123/00 Field of Search 260/564 RF, 501.14

References Cited OTHER PUBLICATIONS Larizza et al. J Org. Chem, Vol. 29, pp 3697-3700 I964)v Primary ExaminerGerald A. Schwartz {57] ABSTRACT 8 Claims, N0 Drawings NEW AMINOPHENYLAMIDINES, THEIR PRODUCTION AND THEIR MEDICINAL USE This is a division of application Ser. No. 399,8 l 3 filed Sept. 24, l973, which itself is a divisional of Ser. No. 151,575 filed June 9, l97l, now Pat. No. 3,855,292.

The present invention relates to new aminophenylamidines and -cycloamidines and salts thereof, to processes for their production, and to their use as medicines, especially as parasiticides.

Acylaminophenylformamidines, such as N-(pacetamidophenyl )-N ',N '-dimethylformamidine (U.S. Pat. No. 3,l84,482) are already known. This compound, as well as other formamidine derivatives, are, however, ineffective against helminths. Furthermore, N-phenylacetamidines, such as N-(p-chlorophenyl )-N', N'-dimethylacetamidine, are known. These compounds are also ineffective against helminths.

This invention provides aminophenylamidines and aminophenylcycloamidines of the general formula:

in which:

R is a hydrogen atom or a straightor branchedchain alkyl, alkoxy alkyl or alkenyl group;

R and R are the same or different and are each a hydrogen, fluorine, chlorine or bromine atom or a straightor branched-chain alkyl, alkenyl, or alkoxy group or a cyano or trifluoromethyl group;

R is a straight or branched-chain alkyl or alkenyl group or a cycloalkyl group; and

either R is a straightor branched-chain alkyl, alkenyl or alkoxy group; and

R is a hydrogen atom or a straightor branchedchain alkyl, alkenyl, alkynyl or alkoxy group;

R and R together with the amino nitrogen atom and the amidino carbon atom form a five, six or sevenmembered ring;

and their salts.

These aminophenylamidines and -cycloamidines and their non-toxic salts are useful for combating parasites, especially helminths, in human and veterinary medicine.

Alkyl and alkoxy groups R preferably contain l to 5, especially 1 or 2, carbon atoms, and the alkenyl group R preferably contains 2 to Scarbon atoms.

Alkyl groups R preferably contain l to 5, most preferably l or 2, carbon atoms, and alkenyl groups R gen erally contain 2 to 5, preferably 2 or 3, carbon atoms.

Alkyl and alkoxy groups R and R preferably contain 1 to 6, especially l to 3, carbon atoms, and alkenyl groups R and R preferably contain 2 to 6, especially 2 to 4, carbon atoms.

Alkyl and alkoxy groups R preferably contain l to 4, especially 1 to 3, carbon atoms. The alkenyl and alkynyl groups R preferably contain 2 to 4 carbon atoms.

If R and R together with the amine nitrogen atom form a S-membered to 7-membered ring, R and R together preferably represent the group (CH in which n represents 3, 4 or 5.

The alkyl groups R preferably contain 1 to 5, especially l to 3, carbon atoms, and the alkenyl groups R preferably contain 2 to 5, especially 2 or 3, carbon atoms. The cycloalkyl group R preferably possesses 3 to 7 carbon atoms.

The active substances according to the invention are basic in character. They can be used as free bases or in the form of their salts, for example hydrohalides, such as, for example, hydrochlorides, sulphates, phosphates, nitrates, acetates, naphthalene disulphonates or pamoates, i.e., the salts with methylene-bis-(Z- hydroxynaphthoic acid-3). The preferred salts are the hydrochlorides.

Particularly preferred compounds are those of the general formula (1 in which:

R is a hydrogen atom or an alkyl or alkylene group containing up to three carbon atoms;

R" is a hydrogen, chlorine or bromine atom or a methyl or cyano group;

R is a hydrogen, chlorine or bromine atom or an alkyl group with up to three carbon atoms or a methoxy, trifluoromethyl or cyano group;

R is methyl or ethyl group; and

either R is a methyl or ethyl group or a cycloalkyl group with 3 to 6 carbon atoms; and

R is an alkyl or alkoxy group with l to 3 carbon atoms;

R and R together are a (CH.;),,, group, m being a whole number from 3 to 5;

and their salts.

The invention further provides four processes designated as (a), (b), (c) and (d) for the production of the new aminophenylamidines and -cycloamidines and their salts.

Process (0) comprises reacting an aniline derivative of the general fonnula with a carboxylic acid amide or thioamide of the general formula:

or with a salt or a reactive derivative thereof. in general formulae (2) and (3) W is an oxygen or sulphur atom and R, R' and R to R are as defined above.

The reaction is optionally carried out in the presence of a condensation agent. The reaction product can be isolated in the form of one of its salts or in the form of a free base, and then optionally converted into any other desired salt.

As salts of the carboxylic acid amides (3) there are to be understood both salts with organic acids, (for example, the acetates) and salts with inorganic acids (for example the hydrohalides or sulphates).

By reactive derivatives of the amides (3) there are, for example, to be understood derivatives which are obtained by reaction of an amide or thioamide of the general formula (3) with an inorganic acid (for example, hydrochloric acid, boron trichloride or sulphuric acid) or with an inorganic or organic acid halide (for example, phosphorus oxychloride, phosphorus pentachloridc, phosgene, thionyl chloride, benzoyl bromide, p-toluenesulphonyl chloride or a mixture of phosgene/aluminium chloride, or phosgene/hydrogen chloride or phosgene, phosphorus oxychloride) or with a trialkyloxonium fluorborate (l carbon atoms per alkyl group) or with a dialkyl sulphate (l v 5 carbon atoms per alkyl group) or an alkyl halide l 5 carbon atoms).

As condensation agents that can be employed in process (u), there may for example be mentioned:

Inorganic acids (for example, hydrochloric acid, boron trichloride, sulphuric acid) or inorganic or organic acid halides (for example phosphorus oxychloride, phosphorus pentachloridc, phosgenc, thionyl chloride. benzoyl bromide, p-toluencsulphonyl chloride or a mixture of phosgene/aluminium chloride, or phosgene/hydrogen chloride or phosgene/phosphorus oxychloride) or trialkyloxonium fluorboratcs (l to 5 carbon atoms per alkyl group) or dialkyl sulphates l to 5 carbon atoms per alkyl group) or alkyl halides l to 5 carbon atoms).

When a thioamide is used, Le. W =sulphur in general formula (3 a desulphurizing agent, for example, HgO, Ag O or Hg(CN can be used advantageously in addition to one of the above-mentioned condensation agents, or without one of these condensation agents.

The reaction components (2) and (3) are preferably employed in the stoichiometrically required amounts.

The reaction can be carried out in any inert organic solvent; among such solvents, aromatic, optionally halogenated, hydrocarbons, for example, benzene, toluene or dichlorobenzcne; optionally chlorinated aliphatic hydrocarbons, for example methylene chloride and chloroform; tetramethylene-sulphone, and lower aliphatic alcohols, for example, methanol and ethanol, should be mentioned.

The reactants are preferably brought together at room temperature (about C) and, if appropriate, are warmed to between and l5()C, preferably 80 to 120C, in order to complete the reaction.

The success of the reaction does not depend on the sequence in which the reactants are brought together. The new compounds are isolated in the customary manner.

Process (b) comprises reducing a nitrophenylamidine or -cycloamidine of the general formula:

R5 0 N N=c N// (4) or a salt thereof, to obtain an aminophenylamidine or -cycloamidine, of the general formula:

i.e. a compound of general formula l in which R is hydrogen. This product is then, if a compound of general formula (I) is required in which R is not hydrogen, either i. alkylated with an alkylating agent of the general formula ii. alkylated reductively with an oxo compound of the general formula:

to obtain a Schiff base which is reduced to give the required aminophenylamidine, -cycloamidine or salt.

In the above general formulae (4), (6) and (7), R, R, R to R are as defined above, B is a reactive ester group or a halogen atom; R is a straight-chain or branched alkyl or alkenyl group; R is a hydrogen atom or an alkyl group: and R is an alkyl group.

Straight-chain or branched alkyl groups R preferably contain 1 to 5 carbon atoms, especially 1 or 2 carbon atoms.

Halogen atoms B are preferably chlorine or bromine atoms. Reactive ester groups B are, for example, my]- sulphonyloxy, for example, benzenesulphonyloxy or toxyloxy or alkylsulphonyloxy, for example methanesulphonyloxy, or alkoxysulphonyloxy (preferably with l or 2 carbon atoms in the alkyl or alkoxy group).

The alkyl groups R preferably contain l to 5, especially l to 4, carbon atoms and the alkyl groups R preferably contain l to 5, especially 1 or 2, carbon atoms.

The nitrophenylamidines of general formula (4) and their salts can be reduced by any suitable method.

The reduction can advantageously be effected catalytically, for example with Raney nickel as the catalyst, optionally in the presence of a solvent, such as an alcohol, for example methanol or ethanol, a solution of hydrochloric acid in ethanol, or an ether for example tetrahydrofuran, at a temperature of to l00C, preferably of 20 to 80C, optionally under pressure, for example at l to lOO, preferably 60 to 80, atmospheres gauge.

The reduction can also be carried out with zinc/hydrochloric acid and stannous chloride, preferably in an aqueous medium (water).

Furthermore, the reduction can be carried out with sodium sulphide, for example in an alcohol, for example, methanol and ethanol, or in an ether, for example, in tetrahydrofuran, at temperatures of 20 to 100C, preferably at the boiling point of the solvent.

Further reducing agents which can be used are com plex metal hydrides, such as, for example, sodium boranate in alcohol (preferably ethanol)/water, at temperatures of, preferably, 20 to 80C.

In process b (i) l to 2 mols of the alkylating agent of general formula (6) are preferably employed per mol of the intermediate compound Examples of suitable solvents for use in step (i) are water, alcohols, for example, methanol or ethanol, ketones for example, acetone, ethers for example, tetrahydrofuran, aromatic hydrocarbons, for example, benzene or toluene, or mixtures of these solvents. An increase in the yields can be achieved by the addition of auxiliary bases such as, for example, sodium hydroxide, sodium and potassium carbonate, pyridine or triethylamine.

The reaction is carried out at 0 100C, preferably at 10 to 40C.

In process 12 (ii) the reactants (5) and (7) are preferably employed in approximately molar amounts. Solvents which can be used for this reaction, which is carried out at 0 to l0OC, preferably at about to 60C, are, for example, alcohols for example, methanol or ethanol, ethers for example, tetrahydrofuran, and aromatic hydrocarbons, for example, benzene or toluene. The Schiffs base obtained in this manner is hydrogenated, optionally being isolated, by any suitable method. For instance, the base may be catalytically hydrogenated, for example with Raney nickel as the catalyst. The catalytic reduction is preferably carried out at room temperature (about 20C) and, and optionally under pressure l to 80 atmospheres gauge, preferably 60 atmospheres gauge). As a solvent an alcohol, for example methanol and ethanol, an aromatic hydrocarbon, for example, benzene and toluene, or an ether, for example, tetrahydrofuran, can be used.

The reduction of the Schitfs base can also be effected by means of a complex metal hydride (approximately stoichiometrically required amounts), for example, sodium borohydride. In this case the reaction is carried out at temperatures of 20 to 80C. Here, alco hols, for example methanol and ethanol, optionally in admixiure with water, are preferably used as solvents.

Process (6) comprises reacting an aminophenylamidine or -cycloamidine of the general formula:

Le. a compound of the general formula 1 in which R is hydrogen, with an aliphatic or aromatic aldehyde to obtain a Schiff base quaternising the Schiff base with an alkylating agent of the general formula:

and subsequently hydrolytically splitting off the aldehyde portion of the product. If a salt is required this is then produced in any suitable manner.

In general formulae (5) and (6), R, R to R and B are as defined above.

In process (0), the compound of the general formula (5) is reacted with any suitable aldehyde, for example, acetaldehyde or benzaldehyde, according to any suitable method, to give the Schiff base. The reactants are preferably employed in molar amounts. The reaction temperatures are preferably between 0 and 80C, pref erably between 20 and 40C. Any inert organic solvent may be used, for instance, an alcohol, for example methanol and ethanol, an aromatic hydrocarbon, for example benzene and toluene, or an ether, for example, tetrahydrofuran.

The Schiff base is quaternised, optionally after being isolated, by means of the alkylating agent (6) by any suitable method, preferably at temperatures between 20 to l00C, especially between to C Any inert organic solvent, for example benzene, toluene and tetrahydrofuran can be employed. The subsequent hydrolysis is preferably carried out without isolation of the quaternised Schiff base, preferably at temperatures between 20 to 100C, especially between 40 and C, and preferably in an aqueous alcohol, especially ethanol.

Process (d) comprises hydrolytic splitting of an acylaminophenylamidine or -cycloamidine of the general formula:

in which R, R and R to R are as defined above and R" is an acyl or acyloxy group, preferably with l 5 carbon atoms.

The hydrolytic splitting is carried out by any suitable method; many such methods are known in the art.

The hydrolysis is preferably carried out in the presence of a strong acid, such as hydrochloric acid or sulphuric acid. Water, or a mixture of water with an alcohol, is used as a solvent. The hydrolysis is preferably carried out at the boiling point of the solvent.

The following Examples illustrate the process according to the invention for the production of the new aminophenylamidines and cycloamidines.

All temperatures are given in degres centigrade (C All starting compounds are known or are obtainable by known processes.

tlnm-rhtlacctamidine in 1250 ml of ethanolic hydrolution, the base which separates out is extracted with ether, the extract is evaporated, and the residue is distilled in vacuo; the product is N-(4-aminophenyl)- N,N'-dimethylaeetamidine, boiling point 158 165, melting point 93 95 (from ethyl acetate); yield 426.5 g, monohydrochloride, melting point 273 274.

The following compounds are obtained by analogous processes:

chloric acid (3.3 molsl are hydrogenated with the aid of Raney nickel as the catalyst. at 70 80 and 80 to 100 atmospheres gauge hydrogen pressure. The mixture is evaporated in vacutx the residue is taken up in water and rendered alkaline with sodium hydroxide so- The following compounds are produced in accor dance with the method described in Example I, by reduction of 2-(nitro-phenylimino)azacycloalkanes:

EXAMPLE 3 23 g of isobutyraldehyde are added dropwisc, at 20, to 53 g (03 mol) of N-(4-an1inophcnyl)-N, N- dimethylacetamidine, dissolved in 500 ml of benzene, the mixture is heated for 7 hours whilst connected to a water separator, and the N-(4- isobutylideneaminopheny])-N', N- dimethylacetamidine is distilled in vacuo; boiling point M 156 160. 8.3 g (0.066 mol) of dimethyl sulphate are added to 13 g (0.056 mol) of this compound, dissolved in 150 ml of benzene, the mixture is heated for one hour under reflux, the benzene is decanted off, the residue is taken up in 50 ml of 50% strength ethanol,

EXAMPLk and the mixture is heated for one hour under reflux. After evaporation in vacuo, and treatment of the resi- (CHM due with sodium hydroxide solution, the free base is ex- RLNH N tracted with ether and distilled: boiling point 155 160, hydrochloride, melting point 226228. N

The following compounds are produced by analo- IV gous processes: R

Ill R R R11! R1 N 1131 R'/ R1! R"R'N R' R" R R R'" Boiling point] mm Hg N 2Cl H CH CH,, CH l7(l/().S 4H .,(:HN 2Br H CH CH5 CH 1711"}115 4-H ,L, HN 2 C1 H CH. CH CH,, 172%.: 4- H,,C, HN H H CH CH CH 1 fir/1115 1 =1HN H H CH CH CH 17 1 "/0115 j: ICCPl ),I:gHN H H CH:, CH CH l69/(J.6 1 H H CH, CH, CH. 17R(, =HCI CHZ -HN 1 s .1 /)4 =1 HN H H CH1, OCH CH 162%; 4 H, C-H1-1 2Cl H CH OCH, (H l78/ll,6 4CH;,OC H H CH CH CH IMF/(L2 CH2HN EXAMPLE 4 n R'NH R' RH R" Boiling point/mm Hg 3 4-CH -NH 2-Cl H CH 191/0.2 3 4C,H,-,NH 2 C1 H CH, ma /11,3 3 4C,H, NH H H CH; I83/U.3 3 4-CH, NH H H C. H, l86/U.2 N 3 4-CH,:NH 2 c1 H (:H; 191M111 4 4- CH,, NH H H (2H,, 1s3/0.3 H1 z a 4--CH1|NH 2-0 H CH 202%.: 5 4CH -NH 2-Cl H (H 2121 111 5 4-CH;.-NH H H L'H lua /11.2

35 g of the N-(4-isobutylideneaminophenyl)-N,N'- 6Q dimethylacetamidine obtained according to Example 3, dissolved in 250 ml of tetrahydrofuran, are hydroge EXAMPLE 6 nated with Raney nickel as the catalyst. at 20 50 and atmospheres gauge of hydrogen. After filtering off H CH 3 the catalyst, and distilling, 17.5 g of N-(4- isobutylaminophenyl )-N',N-dimethylacetamidine. boiling point M 138145, are obtained.

dered alkaline with sodium hydroxide solution, and the 5 aqueous phase is extracted with a mixture of ether and chloroform. After distillation, 12 g of N-(4- aminophenyl )-N ',N '-dimethylacetamidine, boiling point l58l65, melting point 9395, are obtained.

The fact that the new aminophenylamidines and cycloamidines and their salts show a strong and wideranging anthelmintic activity is surprising and unforeseeable.

The new compounds are substantially more effective than other known anthelmintics of the same general action, such as, for example, bephenium hydroxynaph thoates, l,4-phenylene-diisothiocyanate, perchloroethylene, thiabendazole and parbendazole.

Special attention is drawn to the fact that excellent results are achieved with a single administration of the new compounds.

The provision of the invention of the new compounds constitutes a substantial extension of the available range of anthelmintics.

In particular, the compounds manufactured according to the invention for example display a surprisingly good and broad action against the following helminths (nematodes and cestodes):

l. Nematodes l. Ancylosroma caninum, Uncinaria stenocephala and Bunusmmum trigonocephalum (hookworms) from the family of the Ancyclostomatidae;

2. Huemonchus contortus, Tricltosrrongylus colubrflormis, Cooperia punclara, Osterlagia circumcincta, Nipposzrongylus muris and Nematospiroides dubius (worms of the stomach and small intestine) from the family of the Trichostrongylidae;

3. ()esoplzagoslomum columbianum and Cliaberria ovina (worms of the large intestine) from the family of the Strongylidae;

4. Srrongyloides ratti (dwarf threadworms) from the family of the Rhabditidae;

S. Toxocara canis, Toxascaris leom'na and Ascaris suum larvae (coilworms) from the family of the Ascarididae;

6. Aspiculuris tetraptera (maggot worms) from the family of the Oxyuridae;

7. Heterakis spumosa from the family of the Heterakidae;

ll. Cestodes.

l. Hymenolepis nanu and Hymenolepi's microstoma (tapeworms) from the super-family of the Taenioidea.

The action of the new compounds was tested in animal experiments, after oral and parenteral administration to test animals severely infected with parasites. The dosages used were tolerated very well by the test animals.

The unexpected superiority of the compounds according to the invention, as well as their excellent ac tion, is shown by the examples of Tests A D (Tables l to 4).

EXAMPLE A Hookworm Test/Dogs Dogs experimentally infected with Ancylosroma caninum were treated after the end of the pre-patent period of the parasites.

The amount of active compound was administered orally, as the pure active compound or dissolved in 10% strength lactic acid, in gelatine capsules.

The degree of action was determined by counting the worms expelled after treatment and the worms remaining in the test animal after dissection, and calculating the percentage of worms expelled.

The active compounds tested, the dosages used, and the action are summarised in the table which follows.

Table l Hookwom Test/Dogs Table 1 -Continued Hookworm Test] Dogs Active compounds Dose A ction mg/kg in '7:

Q o cH, 1-1 (cH,.). -c|-i Q *1 60 46 HtCi IN 0 [00 77 J H (22) N OCH 200 93 I I I I l 3 l ()0 U N N S J Active compounds according to the invention Literature: Ruwes. DA I96] The activity of Buphcnium Hydrocynuphthoutc against Huokuorms in the Dog Vetv Rec, 73 l6), 390-392 Litemturcl 'lhetxhridcx, VJ and M. lvudcrmun [96K Purhundazolc in the Treatment of Intestinal Nematodes of Dog; and Monkeys Vet. Medv 63 l Ill), 985.

EXAMPLE B The amount of active compound was administered orally, as pure active compound, in gelatine capsules H k T /sh The degree of action was determined by counting the Sheep experimentally infected Bunostomum 65 worms expelled after the treatment and the worms ['6- trigonocephalum were treated after the end of the pre manning in the test animals, after dissection, and calcuatem eri d f th parasites. lating the percentage of worms expelled.

l able Z EXAMPLE D Coilworm Test/Dog Hookworm Test/Sheep Attu e compounds Dose Action mg/kg in 9:

(9H. tH.

Base 1.5 95 H. .\'=(N on Base 10 um Hydrochloride 5 100 ("H l'll i Q- w; an m 97 EXAMPLE C Dogs naturally infected with Toxocam canis or Tuxascarts eum'nu were treated orally. The amount of active compound was administered orally, as pure active com pound or as a l07r strength solution in lactic acid, in gelatine capsules.

The degree of action is determined by counting the worms expelled after the treatment and the worms remaining in the test animals, after dissection. and calculating the percentage of worms expelled.

The active compounds tested, dosages used and ac- 35 tion are summarised in the table which follows.

Table 4 Active Compounds C'oilworm Test/Dog Parasite Dose Action mg/kg in V1 H C To xocara 2.5 l ()0 CEH /CH; Toxocara 10.0 M N=CN .HCI Toxascaris 10.0 80

The active compounds tested, the dosages used and the action are shown in the table which follows.

Table 3 Test on \Vorm of Large Intestine/Sheep Active Compound Dose Action mg/kg in f;

In general it has proved advantageous to administer amounts of 0.1 to 50 mg of the new compounds per kg of body weight per day in order to achieve effective results.

Nevertheless it may at times be necessary to deviate from the amounts mentioned, and in particular to do so as a function of the body weight of the test animal or of the nature of the method of administration, but also because of the variety of animal and its individual behaviour towards the medicament or because of the nature of the formulation of the latter and the point in time. or interval. at which it is administered. Thus. it

may in some cases suffice to use less than the abovementioned minimum amount, whilst in other cases the upper limit mentioned must be exceeded. Where major amounts are administered, it may be advisable to divide these into several individual administrations over the course of a day. The same dosage range is envisaged for administration in human medicine and in veterinary medicine. The general sense of the other comments made above also applies.

As stated above, this invention also relates to the pharmaceutical use of the new aminophcnylamidines and -cycloamidines and their non-toxic salts.

Accordingly, the present invention provides a phar maceutical composition containing as an active ingredient at least one of the new aminophenylamidines and -cycloamidines ofthe general formula l given above, or a non-toxic salt thereof, in admixture with a pharma ceutically acceptable solid or liquid diluent or carrier as hereinafter defined.

[n the present specification the expression *pharnia ceutically acceptable diluent or carrier" means a nontoxic substance that when mixed with the active ingre dient or ingredients renders it suitable for administration. The expression preferably excludes water and low-molecular weight organic solvents commonly used in chemical synthesis, except in the presence of other pharmaceutically necessary ingredients such as salts in correct quantities to render the composition isotonic, buffers, surfactants, colouring and flavouring agents, and preservatives. Examples of suitable liquid and solid diluents and carriers are the following:

Buffered aqueous solutions; isotonic saline aqueous solutions; non-toxic organic solvents; such as paraffins, (for example petroleum fractions); vegetable oils (for example groundnut and sesame oils); alcohols. (for example ethyl alcohol or glycerol); glycols (for example propylene glycol or polyethylene glycol); solid excipients, for example, natural ground rock (for example kaolins, aluminas, talc or chalk), synthetic rock powders (for example highly disperse silica or silicates); and sugars (for example unrefined sugar, lactose and glucose). Examples of pharmaceutical compositions according to the invention are ointments, pastes, creams, sprays, lotions, aqueous suspensions, emulsions and solutions, elixirs, syrups, granules and powders, either freeflowing or compressed into tablets.

The compounds and pharmaceutically acceptable salts of the present invention may be administered perorally.

One group of preferred pharmaceutical compositions of the invention are therefore those adapted for oral administration. The diluents and carriers used are preferably therefore those that adapt the active ingredient or ingredients for oral administration. Examples of such diluents and carriers are solid vehicles, excipients and lubricants such glucose, lactose and sucrose, corn and potato starch, sodium carboxyrnethyl cellulose, ethyl Cellulose and cellulose acetate, powdered gum tragacanth, gelatin, alginic acid, agar, stearic acid, sodium, calcium and magnesium stearates, sodium lauryl sulphate, sodium citrate, calcium carbonate, and di calcium phosphate.

The pharmaceutical compositions of the invention may also contain other non-toxic adjuvants and modifiers such as dyes, surfactants, for example, emulsifiers, such as non-ionic and anionic emulsifiers (for example polyoxyethylene-fatty acid esters, polyoxyethylenefatty alcohol ethers, alkylsulphonates and arylsulphonates), and dispersing agents [for example lignin, sulphite waste lyes, methylcellulose, starch and polyvinyl pyrrolidone) perfumes, flavouring agents, preservatives and biocides.

The compounds and pharmaceutically acceptable salts of the invention may also be administered parenterally, in particular subcutaneously. A group of preferred pharmaceutical Compositions of the invention are therefore those adapted for parenteral injection. The diluents and carriers used are therefore preferably those that adapt the active ingredient for parenteral administration. Examples of such diluents and carriers are solvents and suspending diluents such as water and water-miscible organic solvents, in particular sesame oil, groundnut oil, aqueous propylene glycol, and N.N'- dimethyl formamide. Examples of pharmaceutical compositions of the invention are sterile isotonic saline aqueous solutions of the active ingredient, which may be buffered with a pharmaceutically acceptable buffer and are preferably pyrogen-frce.

The pharmaceutical compositions of the invention generally contain 0.5 to 90 wt. "/1 of a new aminophenylamidine or -cycloamidine of the invention or a non-toxic salt thereof,

The present invention also provides medicaments in dosage unit form as hereinafter defined comprising as an active ingredient at least one aminophenylamidine or -cycloamidine of general formula l given above or a non-toxic salt thereof, either alone or in admixture with a pharmaceutically acceptable solid or liquid diluem or carrier. In this case the diluent or carrier is preferably as defined above but can also be water or an other common solvent.

The expression medicament in dosage unit form as used in the present specification means a medicament in the form of discrete portions each containing a unit dose or a multiple or sub-multiple ofa unit dose of the active ingredien'ds); for example. one, two, three of four unit doses or a half, a third or a quarter of a unit dose. A unit dose" is the amount of the active ingredient( s) to be administered on one occasion and will usually be a daily dose, or for example a half, a third, or a quarter of a daily dose depending on whether the medicament is to be administered once or, for example, twice, three times, or four times a day.

The discrete portions constituting the medicament in dosage unit form can include a protective envelope. The active ingredient can be undiluted and contained in such an envelope, or can be mixed with a pharmaceutically acceptable solid or liquid diluent or carrier as defined above. Such portions can for example be in monolithic coherent form, such as tablets, lozenges, pills, suppositories, or dragees; in wrapped or concealed form, the active ingredients being within a protective envelope, such as wrapped powders, cachets, sachets, capsules, or ampoules; or in the form of a sterile solution suitable for parenteral injection, such as ampoules 0f buffered, isotonic, sterile, pyrogen-free aqueous solution; or in any other form known in the art,

As stated above, it is preferred to administer the new aminophenylamidines and -cycloamidines of general formula l or their salts perorally. Preferred medicaments in dosage unit form according to the invention are therefore those adapted for oral administration, such as tablets, pills, dragees, capsules, and cachets, as well as wrapped powders containing the active ingredient in powdered form with a powdered diluent or carrier for suspension in water before being taken.

As stated above it is also possible to administer the new aminophenylamidines and -cycloamidines parenterally. A further group of medicaments in dosage unit form according to the invention are therefore those adapted for parenteral injection, such as ampoules containing a measured quantity of a sterile isotonic saline injectable aqueous solution of the new active ingredicm, which may be buffered with a pharmaceutically acceptable buffer and are preferably free of pyrogens.

The preferred unit dose for administration of the medicaments of the invention is 50 2,250 mg. of active ingredients. This will normally be administered once daily.

The invention further provides a method of combating parasitic infestation in an animal which comprises administering to the animal (preferably parenterally or perorally) an aminophcnylamidine or -cycloamidine or a non-toxic salt thereof, a pharmaceutical composition or a medicament in dosage unit form according to the invention.

The administration is preferably carried out orally, but may also be carried out parenterally, in particular subcutaneously.

What we claim is:

l. A compound of the formula:

wherein R is hydrogen, alkyl of l to carbon atoms, alkoxyalkyl of 2 to 5 carbon atoms or alkenyl of 2 to 5 carbon atoms;

each of R and R", independently of the other, is fluoro, chloro or bromo, or one is hydrogen and the other is fluoro, chloro or bromo;

R is alkyl of 1 to 5 carbon atoms;

R is alkyl of l to 4 carbon atoms, alkenyl of 2 to 4 carbon atoms, alkynyl of 2to 4 carbon atoms, or cycloalkyl of 3 to 6 carbon atoms; and R is hydrogen, alkyl of l to 5 carbon atoms or alkenyl of 2 to 5 carbon atoms; or a salt thereof of a pharmaceutically acceptable acid. 2. A salt of a compound of claim I wherein said salt is selected from the group consisting of hydrohalides, sulphates, phosphates, nitrates, acetates, naphthalene disulphonates and pamoates.

3. A compound according to claim 1 wherein R is alkyl.

4. A compound according to claim 1 wherein R is hydrogen or alkyl of l to 3 carbon atoms; R is chloro or bromo; R is chloro or bromo, or one of R and R is hydrogen and the other is chloro or bromo; R is methyl or ethyl; R is alkyl of l to 3 carbon atoms; and R is methyl or ethyl. 5. The compound according to claim I wherein R is methyl; R is Z-chloro; R is hydrogen; R is methyl; R is methyl; and R is methyl. 6. The compound according to claim I wherein R is methyl; R is Z-bromo; R is hydrogen; R is methyl; R is methyl; and R is methyl. 7. The compound according to claim 1 wherein R is ethyl; R is 2-chloro; R is hydrogen; R is methyl; R is methyl; and R is methyl. 8. The compound according to claim 1 wherein R is methyl; R is 2-chloro; R is hydrogen; R is methyl; R is methyl; and R is methoxy. 

1. A COMPOUND OF THE FORMULA:
 2. A salt of a compound of claim 1 wherein said salt is selected from the group consisting of hydrohalides, sulphates, phosphates, nitrates, acetates, naphthalene disulphonates and pamoates.
 3. A compound according to claim 1 wherein R5 is alkyl.
 4. A compound according to claim 1 wherein R1 is hydrogen or alkyl of 1 to 3 carbon atoms; R3 is chloro or bromo; R4 is chloro or bromo, or one of R3 and R4 is hydrogen and the other is chloro or bromo; R is methyl or ethyl; R5 is alkyl of 1 to 3 carbon atoms; and R6 is methyl or ethyl.
 5. The compound according to claim 1 wherein R1 is methyl; R3 is 2-chloro; R4 is hydrogen; R is methyl; R5 is methyl; and R6 is methyl.
 6. The compound according to claim 1 wherein R1 is methyl; R3 is 2-bromo; R4 is hydrogen; R is methyl; R5 is methyl; and R6 is methyl.
 7. The compound according to claim 1 wherein R1 is ethyl; R3 is 2-chloro; R4 is hydrogen; R is methyl; R5 is methyl; and R6 is methyl.
 8. The compound according to claim 1 wherein R1 is methyl; R3 is 2-chloro; R4 is hydrogen; R is methyl; R5 is methyl; and R6 is methoxy. 